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EP1390015A1 - Geschmacksverdeckung von stark wasserlöslichen arzneimitteln - Google Patents

Geschmacksverdeckung von stark wasserlöslichen arzneimitteln

Info

Publication number
EP1390015A1
EP1390015A1 EP02734580A EP02734580A EP1390015A1 EP 1390015 A1 EP1390015 A1 EP 1390015A1 EP 02734580 A EP02734580 A EP 02734580A EP 02734580 A EP02734580 A EP 02734580A EP 1390015 A1 EP1390015 A1 EP 1390015A1
Authority
EP
European Patent Office
Prior art keywords
taste
active ingredient
masked
water
cellulose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02734580A
Other languages
English (en)
French (fr)
Inventor
Vijay V. Gupte
Walid Habib
Kris E. Holt
Rajendra K. Khankari
John Hontz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cima Labs Inc
Original Assignee
Cima Labs Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cima Labs Inc filed Critical Cima Labs Inc
Publication of EP1390015A1 publication Critical patent/EP1390015A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • the active ingredients formulated into drug products often have an unpleasant taste. As the solubility of the active ingredient in saliva increases, so too does its offensive taste.
  • taste-masking There are a variety of methods and formulas generally utilized in taste- masking. These include the use of flavors, sweeteners, effervescent systems and various coating strategies. However, for certain drugs, and in particular, antihistamines, such as cetirizine hydrochloride, traditional taste-masking methods have often proven ineffective.
  • Modified celluloses such as hydroxypropylmethyl cellulose (“HPMC”), ethylcelluloses and mixtures of celluloses have been used to produce enteric coatings as well as coatings which can provide a controlled release of an active ingredient. Some of these coatings have also been used in taste-masking.
  • HPMC hydroxypropylmethyl cellulose
  • ethylcelluloses ethylcelluloses and mixtures of celluloses have been used to produce enteric coatings as well as coatings which can provide a controlled release of an active ingredient. Some of these coatings have also been used in taste-masking.
  • One aspect of the present invention is directed to a taste-masked formulation which will reduce or eliminate the release of active ingredient in the mouth and yet will rapidly release the active ingredient in acidic conditions, such as those found in the stomach.
  • These formulations include a taste-masked particles which themselves include (a) a predetermined amount of a particulate active ingredient; (b) at least one coating layer coating the particulate active ingredient.
  • taste-masked, coated active ingredient particles might be used alone or blended with other active ingredients and/or pharmaceutically acceptable excipients to produce a taste-masked formulation.
  • Other aspects of the present invention include methods of preparing taste-masked formulations, methods of using these formulations as well as the taste-masked formulations themselves.
  • the taste-masked formulations of the present invention preferably have slow release rates in conditions normally found in the mouth, such as less than 20% of the active ingredient in the formulation released in basic conditions within three minutes, and fast release rates under conditions normally found in the stomach, such as at least 65% of the active ingredient released in acidic pH within thirty minutes.
  • BEST MODE OF CARRYING OUT THE INVENTION The present invention provides for a taste-masked formulation including taste- masked particles.
  • the taste-masked particles include (1) at least one particulate active ingredient and (2) at least a taste-masking layer surrounding the at least one active ingredient.
  • the taste-masking layer includes predetermined amount of a water-soluble polymer and a water-insoluble polymer, wherein the taste-masked formulation releases less than about 20% of the at least one active ingredient in an aqueous solution at a neutral to basic pH in about 3 minutes and releases at least about 65% of the at least one active ingredient at an acidic pH in about 30 minutes. If more than one layer is used to coat the active ingredient, then, preferably at least the outer layer will have such properties. Alternatively, the layers used, when taken in combination, will have such properties.
  • each of the taste- making layers will have the properties of delayed release of active ingredient in the mouth and rapid release in the stomach, or under such conditions as found therein, and each will contain a mixture of water-soluble and water-insoluble materials, although the specific materials used, and/or their relative proportions, may vary from layer to layer.
  • Other layers which are not intended for taste-masking such as a spacer layer or a layer which prevents reaction between the taste-masking coating and the active ingredient, can also be added. So long as at least are taste masking layer as defined herein is present.
  • the taste- masked formulations release less than about 16%, more preferably less than about 10%, of the at least one active ingredient in an aqueous solution at a basic pH in about 3 minutes and releases at least about 75%, more preferably at least about 85%, of the at least one active ingredient at an acidic pH in about 30 minutes.
  • the active ingredient is in the form of particles.
  • active ingredient particles include, but are not limited to particles, powders, adsorbents, granules, beads, or spheres of the active ingredient alone, in the presence of, in combination with, absorbed in or coated onto a solid support which is preferably in the form of particles, powders, adsorbents, granules, beads, or spheres.
  • Spheres are preferred and particularly useful spheres include sugar spheres, microcrystalline cellulose spheres.
  • the average diameter of the solid support is, if any is used, from about 5 micrometers to about 280 micrometers, and more preferably from about 100 micrometers to about 200 micrometers.
  • the weight ratio of active ingredient and solid support is from about 2:1 to about 1:20, more preferably from about 1.5:1 to about 1:10 and even more preferably from 1.2:1 to about 1 :5.
  • a binder can be included to facilitate the coating of the active ingredient to the solid support.
  • the binder is selected from the group consisting of: hydroxypropyl methylcellulose, HPMC, polyvinyl pyrrolidone, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, povidone, acacia, tragacanth, gelatin, cellulose materials, such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars, and invert sugars, and the like.
  • the binder is provided in an amount sufficient to facilitate adhesion of the entire quantity of active ingredient to the solid support. It can constitute up to about 5% by weight of the coated active ingredient particles, preferably up to about 2% and more preferably up to about 1%.
  • the taste-masking layer(s) has/have from about 2% to about 20% of a water-soluble polymer and from about 80% to about 98% of a water- insoluble polymer based on the total weight of the taste-masking layer, preferably from about 5% to about 18% of a water-soluble polymer and about 82% to about 95% of a water- insoluble polymer.
  • a taste-masking layer includes from about 8% to about 15% of a water-soluble polymer and from about 85% to about 92% of a water-insoluble polymer.
  • the water-soluble polymers contemplated for use in the present application include, but are not limited to, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, and polyethylene glycols.
  • the water- soluble polymer selected is HPMC commercially known as "Opadry ® .”
  • the water-insoluble polymers contemplated for use in the present application include, but are not limited to ethyl cellulose, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose succinate, and shellac.
  • the water-insoluble polymer selected is ethylcellulose commercially known as "Surelease ® .”
  • the taste-masking layer(s) is/are coated onto the active ingredient particles to produce "the coated active ingredient particles.”
  • the present invention is not limited to any thickness or composition of the coating layer(s). Any thickness and any combination of water-soluble polymers or water- insoluble polymers can be used as long as the coating layer meets the performance criteria, such as the desired taste-masking and the desired dissolution profile.
  • the thickness of the coating layer can be defined in terms of the weight gain, e.g., a coating layer thickness of 30% refers to a weight gain of 30% by coating the active ingredient particles, including any solid support, binder or other pharmaceutically acceptable excipient, with at least one taste-masking layer.
  • the thickness of the taste-masking layer(s) is/are generally from about 2% to about 100%.
  • the thickness is from about 5% to about 90%, more preferably from about 10% to about 80%, and most preferably, from about 15% to about 50%.
  • the thickness of the taste-masking layer(s) can be expressed in terms of the percentage of the coating in the taste-masked particles. These two alternative expressions of coating thickness can be easily translated from one to another. It will be appreciated that the upper limit of the coating thickness is affected by the effect it can have on the dissolution of the drug and by practical considerations like cost, weight, size, volume, etc. The lower limit of coating thickness is heavily dictated by its taste-masking ability.
  • the coating should substantially cover the entire surface area of the active ingredient particles.
  • the taste-masking layer can include other ingredients.
  • the coated active ingredient particles contain up to 80% of the at least one active ingredient, preferably from about 0.5% to about 50%, and more preferably from about 2% to about 35%.
  • a advantage of the taste-masked formulation of the present invention is that it can effectively mask the taste of highly water-soluble drugs, and in particular, cetirizine hydrochloride, and at the same time, provide rapid dissolution of the active ingredient in an acidic medium, typically the patient's stomach.
  • the active ingredient is coated in such a way that is sufficient to prevent the dissolution of at least the majority of the active ingredient in a patient's mouth for some defined period of time.
  • the nature of the coating will vary depending upon such factors as the solubility of the particular active ingredient, the taste of the active ingredient and the desired level of taste- masking effect.
  • "effectively masks the taste” requires that that the active ingredient is coated such that less than about 20% of the active ingredient in the formulation is released within three minutes under basic pH (e.g., in the mouth), and at least about 65% of the active ingredient is released in acidic pH within thirty minutes.
  • basic pH includes a pH of as low as about 6.0 and acidic pH includes a pH of less than 6.0.
  • highly water-soluble means that the active ingredient in the formulation has a solubility of at least about 0.05g/ml in an aqueous solution at room temperature, preferably at least about 1.0 g/ml, more preferably at least about 1.5 g/ml and the most preferably at least about 1.6 g/ml.
  • room temperature typically ranges from about 10°C to about 30°C, preferably from about 15°C to about 25°C.
  • the present invention can be used for any active pharmaceutical ingredients, whether in need of taste-masking or not. However, where the underlying active ingredient does not need taste-masking, there may be no need to resort to the added steps of the present invention. For particularly poor tasting drugs, such as cetirizine hydrochloride, where any significant exposure of the active ingredient within the patient's mouth may be unacceptable, the present invention is particularly valuable.
  • the dissolution profile is affected by at least two variables, the weight ratio of water-soluble polymer and water-insoluble polymer in the coating and the thickness of the coating.
  • Other variables which can affect the dissolution profile include the solubility of the active ingredient, the diameters of the support, if any, the tablet size, the tablet hardness, specific surface area of the coated active ingredient particles, materials used, etc.
  • active-ingredients include those having a water solubility of about 0.03 g/ml or more.
  • Active ingredients in accordance with the present invention can be any pharmaceutically active ingredient including, without limitation, abortifacient/ interceptive, ace-inhibitor, ⁇ -adrenergic agonist, ⁇ -adrenergic agonist, ⁇ -adrenergic blocker, ⁇ -adrenergic blocker, adrenocortical steroid, adrenocortical suppressant, adrenocorticotropic hormone, alcohol deterrent, aldose reductase inhibitor, aldosterone antagonist, 5 -alpha reductase inhibitor, anabolic, analeptic, analgesic, androgen, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, anorexic, antacid, anthelmintic, antiacne, antiallergic, antialopecia agent, antiamebic, antiandrogen, antianginal, antiarrhythmic, antiarteriosclerotic, antiarthritic/antirheu
  • the drug is selected from the group consisting of acyclovir; auranofin; bretylium; cytarabine; doxepin; doxorubicin; hydralazine; ketamine; labetalol; mercaptopurine; methyldopa; nalbupbine; nalozone; pentoxifyll; pyridostigmine; terbutaline; verapamil; buserelin; calcitonin; cyclosporin; oxytocin and heparin.
  • the active ingredient is the antihistamine cetirizine hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, pseudoephedrine hydrochloride.
  • the predetermined amount of active ingredient incorporated into each formulation may be selected according to known principles of pharmacy.
  • “Formulation” means an amount of active ingredient and pharmaceutically acceptable excipients combined together which are ultimately incorporated into an overall dosage form.
  • the amount of active ingredient incorporated is a pharmaceutically effective amount.
  • a “pharmaceutically effective amount” is the amount or quantity of an active ingredient which is sufficient to elicit the required or desired therapeutic response. In other words, it is the amount which is sufficient to elicit an appreciable biological response when administered to a patient.
  • the amount of active ingredient used can vary greatly.
  • an active ingredient in each dosage form can be present in an amount of from about 0.1 mg to about 1000 mg, preferably from about 1 mg to about 500 mg and more preferably from about 4 mg to about 200 mg.
  • Conventional amount of pharmaceutically acceptable excipients can be used in this these formulations as well.
  • pharmaceutically acceptable excipients can be used in an amount about 5% to about 90% by weight, based on the weight of the dosage form (pharmaceutically acceptable excipients and coated active ingredient particles). More preferably 10%-50% of said pharmaceutically acceptable excipients can be present.
  • the active ingredient may be used in any particulate form, such as powders, crystals, amorphous particles, granules, spheroid particles, agglomerates, liquid capsule, liquid adsorbed on a solid particles and the like. They may also include solid supports such as a powder, adsorbent, granule, bead, sphere, and the like. Once the desired amount of active ingredient is selected, an amount of solid support sufficient to allow the amount of the active ingredient to be applied thereon is selected and provided. More than one active ingredient may be contained in one or more layers.
  • the active ingredient is applied or preferably uniformly layered or deposited onto the beads through a process such as fluid bed coating, coating in a coating pan, spray coating, spray congealing, or coacervation.
  • the active ingredient layer is dried before applying the taste-masking layer.
  • the taste-masking layer is then coated, absorbed or adsorbed to the active ingredient layer and should substantially completely surround them.
  • the taste-masking layer can be prepared from mixing a water-soluble polymer and a water-insoluble polymer. The amounts of water-soluble polymer and water-insoluble polymer are selected so that effective taste-masking is achieved as well as achieving the desired dissolution profile.
  • dosage forms can be prepared from the taste-masked formulation and at least one pharmaceutically acceptable excipient, which includes, but is not limited to binders, fillers, lubricants, effervescent and/or non-effervescent disintegrants, super disintegrants bulking agents, colors, solvents, flavors adsorbents or absorbants, and the like.
  • Pharmaceutically acceptable excipients also include those disclosed in Authur H. Kibbe, HandBook of Pharmaceutical Excipients, 3d Ed, the content of which is hereby incorporated by reference to the extent permitted.
  • Dosage form includes, but is not limited to orally disintegrating tablets or capsule, soft gel capsule, caplet, slugged capsule, chewable tablet and the like.
  • dosage forms can be prepared using techniques known in the art. Moreover, additional ingredients, such as disintegrants, binders, lubricants, can be added to the dosage form.
  • additional ingredients such as disintegrants, binders, lubricants, can be added to the dosage form.
  • pharmaceutically acceptable excipients can be used in an amount about 5% to about 90% by weight, based on the weight of the dosage form (pharmaceutically acceptable excipients and coated active ingredient particles). More preferably 10%-50% of said pharmaceutically acceptable excipients can be present.
  • any range of numbers recited in the specification or paragraphs hereinafter describing or claiming various aspects of the invention, such as that representing a particular set of properties, units of measure, conditions, physical states or percentages, is intended to literally incorporate expressly herein by reference or otherwise, any number falling within such range, including any subset of numbers or ranges subsumed within any range so recited.
  • Taste-masked particles containing cetirizine which satisfy the criteria of the present invention were prepared by (1) mixing 20.4 grams of cetirizine HCl, 2.9 grams of polyvinyl pyrrolidone and 5.8 grams of hydroxypropyl methylcellulose, (2) coating the mixture of step (1) onto 50 grams of microcrystalline cellulose spheres, having a diameter of 230 micrometer using a fluid bed coater, and then dried. (3) mixing 18 grams of Surelease ® (ethylcellulose produced by Colorcon, Lot Number E719010) and 2.0 grams of Opadry ® (HPMC produced by colorcon, Lot Number YF119053) and (4) coating the mixture of step
  • 500g of cetirizine layered beads were prepared by coating cetirizine to the beads.
  • a coating solution of 833.3g was also prepared by mixing 450g of Surelease Clear containing 25% solids and 12.5g of Opadry with 370.8g of water. Then, the coating solution is coated onto the 500g of cetirizine layered beads and the coated beads were dried.
  • the 833.3g of coating solution on the 500g of cetirizine layered beads represents a coating thickness of about 20%.
  • Example 2 Testing the effectiveness of the coatings containing 80% water-insoluble and 20% water-soluble polymer mixture on masking the taste of cetirizine
  • Cetirizine formulations were prepared generally in the same way as that described in Example 1.
  • the coated beads were compressed into tablets.
  • the tablet size is 300 mg and 3/8 inch.
  • the tablets contain 23.6% of the coated drug, about 56% of mannitol, 5% of aspartame, 5% of crospovidone, 3% of microcrystalline cellulose, 2% of citric acid, 3% of sodium bicarbonate, 0.4% of flavor, 0.4% of color, 0.3% of silicon dioxide, and 1.5% of magnesium stearate.
  • the tablets have hardness of about 30 Newtons. Tablets compressed from the coated spheres were subjected to dissolution testing.
  • # coating thickness of 35% and 40% refer to weight gains of 35% and 40%, respectively.
  • Table 2 shows the results of dissolution experiments for tablets prepared from the coated spheres containing a ratio of 80% Surelease ® (ethylcellulose) and 20% Opadry ® (HPMC) at various coating thicknesses. For each coating thickness, the time and percent dissolution is reported for both basic (pH 7.3) and acidic (0.01N HCl, pH 2.0) conditions. Each of these coating thicknesses meets the criteria that the release of the active ingredient is less than 20% in aqueous solution at a neutral or basic pH in 3 minutes and the release of the active ingredient is more than about 65% in acidic pH in 30 minutes.
  • Example 3 Testing the effectiveness of the coatings containing 85% water-insoluble and 15% water-soluble polymer mixture on masking the taste of cetirizine
  • Cetirizine formulations were also prepared in the same way as that described in Example 2, except the ratio of water-insoluble and water-soluble polymers.
  • the dissolution test results of these formulations are listed in Table 3. Table 3: (85% Water-Insoluble Polymer/15% Water-Soluble Polymer)
  • Table 3 shows the measured results of dissolution tests for tablets prepared from the coated spheres containing a ratio of about 85% Surelease ® (ethylcellulose) and about 15% Opadry (HPMC) at various coating thicknesses. For each coating thickness, the time and percent dissolution is reported for both basic (pH 7.3) and acidic (0.01 N HCl) conditions. A review of the data in Table 3 reveals that all three coating thicknesses meet the performance criteria.
  • Example 4 Testing the effectiveness of the coatings containing 90% water-insoluble and 10% water-soluble polymer mixture on masking the taste of cetirizine
  • Cetirizine formulations were prepared in the same way as that described in Example 2, except the ratio of water-soluble and water-insoluble polymers. The dissolution test results of these formulations are listed in Table 4.
  • Table 4 shows the results of dissolution tests for coated tablets containing about 90% Surelease ® (ethylcellulose) and about 10% Opadry ® (HPMC) at coating thicknesses of 20% and 25%. For each coating thickness, the time and percent dissolution are given for both basic (pH 7.3) and acidic (0.01 N HCl) conditions. The data in Table 4 reveal that of the two thicknesses tested, both yield a desirable dissolution profile while simultaneously providing a more desirable taste-masking effect.
  • Surelease ® ethylcellulose
  • HPMC Opadry ®
  • the present invention can be applied in the taste-masking of pharmaceuticals.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP02734580A 2001-05-31 2002-05-30 Geschmacksverdeckung von stark wasserlöslichen arzneimitteln Withdrawn EP1390015A1 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US29493801P 2001-05-31 2001-05-31
US294938P 2001-05-31
US29500201P 2001-06-01 2001-06-01
US295002P 2001-06-01
PCT/US2002/016908 WO2002096392A1 (en) 2001-05-31 2002-05-30 Taste-masking of highly water-soluble drugs

Publications (1)

Publication Number Publication Date
EP1390015A1 true EP1390015A1 (de) 2004-02-25

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EP02734580A Withdrawn EP1390015A1 (de) 2001-05-31 2002-05-30 Geschmacksverdeckung von stark wasserlöslichen arzneimitteln

Country Status (5)

Country Link
US (1) US20030096791A1 (de)
EP (1) EP1390015A1 (de)
JP (1) JP2004532257A (de)
CA (1) CA2447693A1 (de)
WO (1) WO2002096392A1 (de)

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